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Inhibitory Effect of Gums and Adsorbants Upon the Migration of FD&C Blue No. 1 in Lactose
Inhibitory Effect of Gums and Adsorbants Upon the Migration of FD&C Blue No. 1 in Lactose By JONAH JAFFE* and IRWIN LIPPMA" The dekree of mi ration of FD&C Blue No. 1 on a lactose granulation column was determined. Adtitives to act as dye migration inhibitors were uniform1 incorporated into lactose granulation columns (prior to wetting with aqueous Jye solutions) and evaluated. Tragacanth (1 per cent), acacia 3 per cent), attapulgite (5 per cent), and talc (7 er cent) were effective dye inhi itors at their respective levels. Solka-Floc was stown to have dye migration tendencies, but was still not completely effective at the 9 per cent level.
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ISUAL OBSERVATIONS of commercially availVable uncoated colored tablets reveal the need, in many instances, for an examination into the cause of lack of uniformity of the tablet color and into a method for its improvement. In a recent article (l), the operation of fluidized bed drying was reported to be an effective procedure in improving color uniformity of colored granulations. Aside from the manufacturing techniques involved in mixing, blending, and drying colored granulations, the problem appears to center on those factors influencing the uniformity of applimtion of dyes to a granulation, the most pronounced phenomenon being migration of the dye. When a powder or granulation previously wetted with an aqueous dye solution is being air dried, the solvent rises through the powder by means of capillary action and diffusion and evaporates at the surface. Under these conditions, a hydrophilic dye with little affinity for the powder or granulation would, if present, rise with the aqueous solvent and be deposited at the solidgas interface. This process then could be likened to adsorption chromatography wherein a water soluble dye applied to a weak adsorbant passes through the column with the aqueous eluent. Although texts on tableting (2, 3) recognize the problem of dye migration, no evaluation or treatment of the subject appears to have been reported. It was therefore of interest to determine quantitatively the degree of migration of a dye in a granulation being dried and to examine the inhibitory influence of several additives on dye migration during the drying process.
about 5 minutes.) The colored and dampened material was then hand screened through a 16-mesh stainless steel screen. Clear glass vials of uniform internal diameter (29 mm.) and of uniform height (69 mm.) were then rapidly filled in duplicate to within 5 rnm. of the top of the vial with approximately 29 Gm. of colored granulation. The material was settled by gently tapping the underside of the vial. The uncovered vials were then placed to dry in a dehumidified room held to a relative humidity of 20y0 and a temperature of 25". FD&C Blue No. 1, having a relatively large degree of water solubility, was chosen as representative of the FD&C dyes commonly employed. The adsorptive abilities of the powder and its constituents must be taken into consideration, as we were
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EXPERIMENTAL An aqueous solution of FD&C Blue No. 1a t 0.1% concentration was prepared. To 500 Gm. of lactose U.S.P. (in a Hobart mixer, model N-50)60 ml. of the dye solution was slowly added and mixed t o a reasonably uniform color dispersion. (This required Received July 23. 1963, from the Research Department. Organon, Inc., West Orange, N. J.. and the Product Development Department, A. H. Robins Co.. Richmond, Va. Amptcd for publication August 26, 1963. * Prescnt address: Pharmaceutical Research and Development Division, Organon. Inc.
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3rd
4th
COLUMN SEGMENT
Fig. 1.-Concentration in mg./Gm. of FDLC Blue No. 1 in various segments of a lactose colUrn.
441
442
Journal of Pharmuceii!ical Sciences
interested in examining the migration aspects of the dye. It has been indicated by several authors (4, 5) that a n inverse relationship between solubility and adsorbability appears t o exist. The triphenylmethane group of dyes generally shows better water and polar solvent solubility than the azo, indigoid, and xanthene dyes. F D & C Blue No. 1, a triphenylmethane dye with three sulfonic acid groups, should serve as a dye more difficult t o adsorb onto a column than other triphenylmethane dyes with fewer sulfonic acid groups. The inverse relationship of adsorption from aqueous solutions and the number of sulfonic acid groups present on i i dye molecule has been reported (6). As adsorption takes place better at lower temperatures (7), a temperature of 25“ was chosen in preference to higher oven drying temperatures. A slow uniform rate of drying also precludes the possibility
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C
.16
3
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.12
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0
$ .08 .04
COLUMN S E G M E N T
Fig. 2.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of acacia. Key: A = 2%, B = 3%, C = 4%. of “case hardening” and subsequent retention of moisture within the column. After a period of 5 days, to permit the moisture level t o drop to insignificant levels (less than 0.4% measured on a Cenco moisture balance) and to assure contact of the dye with any adsorbent that may be present, the columns of material were removed by inverting the vials and tapping the sides and glass bottoms smartly. The intact formed cylinder of granulation was then measured off into equal sections and cut with a sharp blade. Each section was then weighed and dissolved in 50 ml. of distilled water. Absorbance readings, using a Beckman model DU spectrophotometer a t a wavelength of 630 ma, were recorded and the dye concentration in milligrams per gram of lactose were calculated (see Fig. l). Since the dye solution is absorbed by the lactose in a sponge-like manner and since the color can be readily washed out of the granulation (as exhibited by the rapid migration of the dye), the process of coloring the lactose is said to be one of “imbibition” and not one of true dyeing (8). This suggested that “colloids which imbibe t o their fullest” (9) might act t o localize the color and prevent migration. “Thickeners,” exemplified by acacia and tragacanth, have
B
C
H N W ”
g gas COLUMN S E G M E N T
Fig. 3.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of tragacanth. Key: A = l % , B = 2 % , C = 3%. been employed in textile dyeing for just this purpose (10). As these gums readily fonn colloidal dispersions, they were incorporated into the columns of lactose in a n attempt t o inhibit the migration of the dye. Solka-Floc, a purified wood cellulose, has been listed as an organic adsorbant (11); this material also has the property of absorbing moisture. These properties led to the inclusion of Soka-Floc as an additive to be evaluated. Adsorptions of dyes on mineral substances have been amply described in the literature (12). Based on their dispersed position throughout a lactose granulation, it was thought that inert adsorbants, such as talc and activated attapulgite, might adsorb and hold the dyes in place, thereby preventing migration of a hydrophilic dye as the water surfaced and evaporated. The experimental procedures employed t o eval-
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g gas COLUMN S E G M E N T
Fig. 4.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columris containing different levels of Solka-Floc. Key: A = 3%, B = 6%, C = 9%.
Vol. 53, No. 4 , April I964
443
uate the effect of gums and adsorbants on the migration of dyes were the same as described above, except t h a t each column now contained a uniformly incorporated additive. The calculated concentrations of the prepared dye solutions added to the different granulations was not exactly 0.1?40for each solution prepared. I t is the relative dye concentration found within each individual column, however, t h a t points to the degree of migration. A level of 3% was first chosen to establish a basis for comparison. Additional concentration levels of the additives were then incorporated and evaluated in a n attempt to determine t h a t level which would be effective in inhibiting the migration of the dpc.
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RESULTS AND DISCUSSION COLUMN SEGMENT
Figures 2 4 offer a visual representation of the results. Uniformity of height of the bars indicates
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gas COLUMN SEGMENT
Fin. 5.-Concentration in mn./Cm. of FD&C Blue-No. 1 in various segments lactose columns containing different levels of talc. Key: A = 3y0, B = 570, C = 770.
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t h e ideal situation of uniformity of color throughout the columns. Figure 4 reveals the concentration of dye found in the upper portions of the column expressed as per cent of total dye recovered from the column. Acacia, a t the 3% level. inhibited the migration of F D & C Blue No. 1 in our lactose column. Tragacanth appears t o be equally effective a t the 1% level. The adsorbants. talc and attapulgite, were also effective, but required a greater concentration of additive than t h a t required for the gums. .4pproximately 5yGof activated attapulgite was comparable in effect t o 7yGtalc. Solka-Floc exhibited migration inhibiting tendencies as shown by the inverse relationship between concentration of additive and con-
Fig. B.-Coneentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of attapulgite. Key: A = 370, B = 470, C = 57”. centration of dye into the upper portions of the column. However, complete inhibition was not found a t the 9% level of additive. Surface area of adsorbant may be a factor influencing the relative abilities of the various additives to inhibit dye migration, but this has not yet been evaluated I t would seem from the above t h a t gums and adsorbants can be successfully employed to inhibit the migration of F D & C Blue No. 1 on a lactose column. I n the order or effectiveness, i t has been found t h a t 1% tragacanth is roughly equivalent to 3y0acacia, which is approximately equivalent to 5y0 attapulgite or 7 7 , talc. Extrapolation of the data in Fig. 4 indicates that Soka-Floc a t the 12-lS’3.0 level might also be a n effective dye migration inhibitor. Thus, i t appears that incorporation of selected gums and mineral adsorbants into formulations of wet granulations inhibits the migration of dycs.
REFERENCES (1) Scott, M. W.. I.ieberrnao, H. A,. Rankell. A. S.. C h o w , P . S., and Johnston, G. W . , THISJ O U R N A L , 52, 284 ( 1 963). (2) Wood. J. K.. “Tablet Manufacture,” J. 8 . Lippincott C o . , Philadelphia, Pa., 1808. p. 86. (3) Little, A.,. and Mitchell. K . A , , “Tablet Making.” Northern Publishing Co., Ltd., Liverpool, England, 1951, p.
--
JZ.
(4) J.undclius, E. F.,Kdloid Z . . 26, 145(1921). (5) Ckxgrievics, G.v., rbid., 28, 253(1921). (6) Vcnkatararnan, K . , “The Chemistry of Synthetic Dyes.” Vol. 2, Academic Press, Ioc., N e w York. N. Y., 1952. p. 1318. 7) Rao. M. R . A , J.Indian Chcrn. SM..12.371(1935). 18) ,V’1ckusta5, T., “The Physical Chemistry of Dycing,” Iotersciencc Publishers lnc. N e w York N. Y. 1854, p. 3. (9 Rockland, P.. biockc’rn.Z.. 23. i78(19&). (lo{ Veokataramao. K . . i b i d . . 1. 289(1952). (11) Cassidy. H . A,. ”Adsorption and Chromatograpby.” lntcrscience Publishers. Inc.. N e w York. N. Y.. 1951. p. 199. (12) I b i d . , p. 183.
b
ISUAL OBSERVATIONS of commercially availVable uncoated colored tablets reveal the need, in many instances, for an examination into the cause of lack of uniformity of the tablet color and into a method for its improvement. In a recent article (l), the operation of fluidized bed drying was reported to be an effective procedure in improving color uniformity of colored granulations. Aside from the manufacturing techniques involved in mixing, blending, and drying colored granulations, the problem appears to center on those factors influencing the uniformity of applimtion of dyes to a granulation, the most pronounced phenomenon being migration of the dye. When a powder or granulation previously wetted with an aqueous dye solution is being air dried, the solvent rises through the powder by means of capillary action and diffusion and evaporates at the surface. Under these conditions, a hydrophilic dye with little affinity for the powder or granulation would, if present, rise with the aqueous solvent and be deposited at the solidgas interface. This process then could be likened to adsorption chromatography wherein a water soluble dye applied to a weak adsorbant passes through the column with the aqueous eluent. Although texts on tableting (2, 3) recognize the problem of dye migration, no evaluation or treatment of the subject appears to have been reported. It was therefore of interest to determine quantitatively the degree of migration of a dye in a granulation being dried and to examine the inhibitory influence of several additives on dye migration during the drying process.
about 5 minutes.) The colored and dampened material was then hand screened through a 16-mesh stainless steel screen. Clear glass vials of uniform internal diameter (29 mm.) and of uniform height (69 mm.) were then rapidly filled in duplicate to within 5 rnm. of the top of the vial with approximately 29 Gm. of colored granulation. The material was settled by gently tapping the underside of the vial. The uncovered vials were then placed to dry in a dehumidified room held to a relative humidity of 20y0 and a temperature of 25". FD&C Blue No. 1, having a relatively large degree of water solubility, was chosen as representative of the FD&C dyes commonly employed. The adsorptive abilities of the powder and its constituents must be taken into consideration, as we were
-
.24
-
.20
-
.16
-
.I2
-
.08
-
.04
-
kl
I*
0
$
EXPERIMENTAL An aqueous solution of FD&C Blue No. 1a t 0.1% concentration was prepared. To 500 Gm. of lactose U.S.P. (in a Hobart mixer, model N-50)60 ml. of the dye solution was slowly added and mixed t o a reasonably uniform color dispersion. (This required Received July 23. 1963, from the Research Department. Organon, Inc., West Orange, N. J.. and the Product Development Department, A. H. Robins Co.. Richmond, Va. Amptcd for publication August 26, 1963. * Prescnt address: Pharmaceutical Research and Development Division, Organon. Inc.
.28
TOP
2nd
3rd
4th
COLUMN SEGMENT
Fig. 1.-Concentration in mg./Gm. of FDLC Blue No. 1 in various segments of a lactose colUrn.
441
442
Journal of Pharmuceii!ical Sciences
interested in examining the migration aspects of the dye. It has been indicated by several authors (4, 5) that a n inverse relationship between solubility and adsorbability appears t o exist. The triphenylmethane group of dyes generally shows better water and polar solvent solubility than the azo, indigoid, and xanthene dyes. F D & C Blue No. 1, a triphenylmethane dye with three sulfonic acid groups, should serve as a dye more difficult t o adsorb onto a column than other triphenylmethane dyes with fewer sulfonic acid groups. The inverse relationship of adsorption from aqueous solutions and the number of sulfonic acid groups present on i i dye molecule has been reported (6). As adsorption takes place better at lower temperatures (7), a temperature of 25“ was chosen in preference to higher oven drying temperatures. A slow uniform rate of drying also precludes the possibility
B
C
.16
3
n
.12
a
0
$ .08 .04
COLUMN S E G M E N T
Fig. 2.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of acacia. Key: A = 2%, B = 3%, C = 4%. of “case hardening” and subsequent retention of moisture within the column. After a period of 5 days, to permit the moisture level t o drop to insignificant levels (less than 0.4% measured on a Cenco moisture balance) and to assure contact of the dye with any adsorbent that may be present, the columns of material were removed by inverting the vials and tapping the sides and glass bottoms smartly. The intact formed cylinder of granulation was then measured off into equal sections and cut with a sharp blade. Each section was then weighed and dissolved in 50 ml. of distilled water. Absorbance readings, using a Beckman model DU spectrophotometer a t a wavelength of 630 ma, were recorded and the dye concentration in milligrams per gram of lactose were calculated (see Fig. l). Since the dye solution is absorbed by the lactose in a sponge-like manner and since the color can be readily washed out of the granulation (as exhibited by the rapid migration of the dye), the process of coloring the lactose is said to be one of “imbibition” and not one of true dyeing (8). This suggested that “colloids which imbibe t o their fullest” (9) might act t o localize the color and prevent migration. “Thickeners,” exemplified by acacia and tragacanth, have
B
C
H N W ”
g gas COLUMN S E G M E N T
Fig. 3.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of tragacanth. Key: A = l % , B = 2 % , C = 3%. been employed in textile dyeing for just this purpose (10). As these gums readily fonn colloidal dispersions, they were incorporated into the columns of lactose in a n attempt t o inhibit the migration of the dye. Solka-Floc, a purified wood cellulose, has been listed as an organic adsorbant (11); this material also has the property of absorbing moisture. These properties led to the inclusion of Soka-Floc as an additive to be evaluated. Adsorptions of dyes on mineral substances have been amply described in the literature (12). Based on their dispersed position throughout a lactose granulation, it was thought that inert adsorbants, such as talc and activated attapulgite, might adsorb and hold the dyes in place, thereby preventing migration of a hydrophilic dye as the water surfaced and evaporated. The experimental procedures employed t o eval-
.24
B
.20
>
C
.16
L
0
6 .12 E .08
.04
rjESW”
g gas COLUMN S E G M E N T
Fig. 4.-Concentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columris containing different levels of Solka-Floc. Key: A = 3%, B = 6%, C = 9%.
Vol. 53, No. 4 , April I964
443
uate the effect of gums and adsorbants on the migration of dyes were the same as described above, except t h a t each column now contained a uniformly incorporated additive. The calculated concentrations of the prepared dye solutions added to the different granulations was not exactly 0.1?40for each solution prepared. I t is the relative dye concentration found within each individual column, however, t h a t points to the degree of migration. A level of 3% was first chosen to establish a basis for comparison. Additional concentration levels of the additives were then incorporated and evaluated in a n attempt to determine t h a t level which would be effective in inhibiting the migration of the dpc.
.12 pl
b t- I
B
C
5
2 .08 g ” 04
RESULTS AND DISCUSSION COLUMN SEGMENT
Figures 2 4 offer a visual representation of the results. Uniformity of height of the bars indicates
B
C
+NU&
gas COLUMN SEGMENT
Fin. 5.-Concentration in mn./Cm. of FD&C Blue-No. 1 in various segments lactose columns containing different levels of talc. Key: A = 3y0, B = 570, C = 770.
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t h e ideal situation of uniformity of color throughout the columns. Figure 4 reveals the concentration of dye found in the upper portions of the column expressed as per cent of total dye recovered from the column. Acacia, a t the 3% level. inhibited the migration of F D & C Blue No. 1 in our lactose column. Tragacanth appears t o be equally effective a t the 1% level. The adsorbants. talc and attapulgite, were also effective, but required a greater concentration of additive than t h a t required for the gums. .4pproximately 5yGof activated attapulgite was comparable in effect t o 7yGtalc. Solka-Floc exhibited migration inhibiting tendencies as shown by the inverse relationship between concentration of additive and con-
Fig. B.-Coneentration in mg./Gm. of FD&C Blue No. 1 in various segments of lactose columns containing different levels of attapulgite. Key: A = 370, B = 470, C = 57”. centration of dye into the upper portions of the column. However, complete inhibition was not found a t the 9% level of additive. Surface area of adsorbant may be a factor influencing the relative abilities of the various additives to inhibit dye migration, but this has not yet been evaluated I t would seem from the above t h a t gums and adsorbants can be successfully employed to inhibit the migration of F D & C Blue No. 1 on a lactose column. I n the order or effectiveness, i t has been found t h a t 1% tragacanth is roughly equivalent to 3y0acacia, which is approximately equivalent to 5y0 attapulgite or 7 7 , talc. Extrapolation of the data in Fig. 4 indicates that Soka-Floc a t the 12-lS’3.0 level might also be a n effective dye migration inhibitor. Thus, i t appears that incorporation of selected gums and mineral adsorbants into formulations of wet granulations inhibits the migration of dycs.
REFERENCES (1) Scott, M. W.. I.ieberrnao, H. A,. Rankell. A. S.. C h o w , P . S., and Johnston, G. W . , THISJ O U R N A L , 52, 284 ( 1 963). (2) Wood. J. K.. “Tablet Manufacture,” J. 8 . Lippincott C o . , Philadelphia, Pa., 1808. p. 86. (3) Little, A.,. and Mitchell. K . A , , “Tablet Making.” Northern Publishing Co., Ltd., Liverpool, England, 1951, p.
--
JZ.
(4) J.undclius, E. F.,Kdloid Z . . 26, 145(1921). (5) Ckxgrievics, G.v., rbid., 28, 253(1921). (6) Vcnkatararnan, K . , “The Chemistry of Synthetic Dyes.” Vol. 2, Academic Press, Ioc., N e w York. N. Y., 1952. p. 1318. 7) Rao. M. R . A , J.Indian Chcrn. SM..12.371(1935). 18) ,V’1ckusta5, T., “The Physical Chemistry of Dycing,” Iotersciencc Publishers lnc. N e w York N. Y. 1854, p. 3. (9 Rockland, P.. biockc’rn.Z.. 23. i78(19&). (lo{ Veokataramao. K . . i b i d . . 1. 289(1952). (11) Cassidy. H . A,. ”Adsorption and Chromatograpby.” lntcrscience Publishers. Inc.. N e w York. N. Y.. 1951. p. 199. (12) I b i d . , p. 183.